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Transcellular spreading of huntingtin aggregates in the Drosophila brain.

ABSTRACT: A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non-cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide-sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

SUBMITTER: Babcock DT

PROVIDER: S-EPMC4593132 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Transcellular spreading of huntingtin aggregates in the Drosophila brain.

Babcock Daniel T DT Ganetzky Barry B

Proceedings of the National Academy of Sciences of the United States of America 20150908 39

A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the D ...[more]

PMID: 26351672

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Project description:Microarray experiments have generally focused on magnitude of gene expression changes in pathological conditions, thereby using the method as a high throughput screen to identify candidate marker genes and/or to validate phenotypic differences. We have used novel strategies to extract additional information from array studies, including expression variability and coordination, from which organizational principles of transcriptomes are emerging. We have reported that expression level, variability and coordination of numerous genes are regulated in brains of Gja1-/- mice with respect to wildtypes. Moreover, expression coordination with Gja1 in wildtypes largely predicted expression regulation in Gja1-/- tissues. We now report a remarkable overlap between regulations in Gja1-/- and Gjb1-/- brains, and that both differ markedly from those in Gja9-/- brain. Since in brain these three connexins are expressed in different cell types (Gja1 in astrocytes, and ependymal and vascular cells, Gjb1 in oligodendrocytes, and Gja9 in neurons and microglia), and because astrocytes and oligodendrocytes may form syncytia coupled by gap junction channels, these observations suggest the existence of distinct connexin-dependent panglial and neuronal transcriptomic networks. Such networks, where linkage partners are rearranged and strengths modified in brains of knockouts, may explain downstream and parallel 'ripples' of phenotypic change resulting from single gene alterations as the composition and interactions of transcription factor networks in the wildtype brain were identified and found to be altered disruption of Gja1 or Gjb1. The transcription factors also formed network hubs with genes from other functional categories, thus allowing regulation of one functional pathway through manipulation of another. Keywords: genetic modification The brain transcriptomes of Gja9(-/-) and Gja9(+/-) P10 mice were compared to that of P10 wildtype mouse using the "multiple yellow" design in which extracts of biological replicas of the same genotype were hybridized with six 27k AECOM mouse cDNA microarrays (4 biological replicas of each genotype). These data were further compared to previously reported data on brain of neonatal wildtype, Gja1(-/-), Gja1(+/-) and Gjb1(-/-) mice (four biological replicas per genotype, reference sample design).

Dataset Information

Transcellular spreading of huntingtin aggregates in the Drosophila brain.

Publications

Transcellular spreading of huntingtin aggregates in the Drosophila brain.

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